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P T. 2017;42(10): 608-613,618-619,650-651

Drug and Device News October 2017

NEW DRUG APPROVALS

Kymriah, CAR T-Cell Therapy For Younger Patients With ALL

The FDA has taken what it calls “historic action” by approving the first U.S. gene therapy. The immunotherapy tisagenlecleucel (Kymriah, Novartis Pharmaceuticals) is indicated for patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse.

Each dose of tisagenlecleucel is a customized treatment created using the individual’s own T cells, which are collected and sent to a manufacturing center. There, they are genetically modified to include a new gene that contains a specific protein (a chimeric antigen receptor [CAR]) that directs the T cells to target and kill leukemia cells that have the antigen CD19 on the surface. Once the cells are modified, they are infused back into the patient to kill the cancer cells.

The safety and efficacy of tisagenlecleucel were demonstrated in one multicenter clinical trial of 63 pediatric and young adult patients with relapsed or refractory B-cell precursor ALL. The overall remission rate within three months of treatment was 83%.

Tisagenlecleucel carries a boxed warning for cytokine release syndrome and neurological events, both of which can be life threatening. Other severe side effects include serious infections, hypotension, acute kidney injury, fever, and hypoxia. Tisagenlecleucel was approved with a risk evaluation and mitigation strategy, and Novartis must conduct a post-marketing observational study involving patients treated with it.

Source: FDA, August 30, 2017

Besponsa for Relapsed, Refractory ALL

The FDA has approved inotuzumab ozogamicin (Besponsa, Pfizer, Inc.) for the treatment of adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL), who previously had few effective treatment options.

Inotuzumab ozogamicin is thought to work by binding to B-cell ALL cancer cells that express the CD22 antigen, blocking the growth of cancerous cells. In a randomized trial, researchers evaluated 218 patients with relapsed or refractory B-cell ALL who had failed one or two prior treatments. Among patients who received inotuzumab ozogamicin, 35.8% experienced complete remission (CR) for a median 8.0 months; among patients who received an alternative chemo therapy regimen, 17.4% experienced CR for a median 4.9 months.

Inotuzumab ozogamicin carries a boxed warning that severe hepatotoxicity, including veno-occlusive disease or sinusoidal obstruction syndrome, has occurred in some patients. The boxed warning also includes an increased risk of death for patients who take inotuzumab ozogamicin after receiving a certain type of stem cell transplant.

Source: FDA, August 17, 2017

Vabomere, a New Antibacterial

An antibacterial combination of meropenem/vaborbactam (Vabomere, The Medicines Company) has received FDA approval for adults with complicated urinary tract infections (cUTI), including pyelonephritis. Meropenem is an antibacterial, while vaborbactam inhibits certain types of resistance mechanisms used by bacteria.

Meropenem/vaborbactam addresses gram-negative bacteria that produce beta-lactamase enzymes, particularly the Klebsiella pneumoniae carbapenemase (KPC) enzyme. KPC-producing bacteria are responsible for a large majority of all U.S. carbapenem-resistant Enterobacteriaceae. Bacteria designated as susceptible to meropenem/vaborbactam include Escherichia coli, K. pneumoniae, and Enterobacter cloacae species complex.

The safety and efficacy of meropenem/vaborbactam were evaluated in a clinical trial among 545 adults with a cUTI, including pyelonephritis. At the end of intra venous treatment with meropenem/vaborbactam, approximately 98% of patients treated with it had cure or improvement in symptoms and a negative urine culture test compared with approximately 94% of patients treated with piperacillin/tazobactam.

Sources: FDA and The Medicines Company, August 30, 2017

Mavyret for HCV

Glecaprevir/pibrentasvir (Mavyret, AbbVie) has received FDA approval as an eight-week, pan-genotypic treatment for patients with hepatitis C virus (HCV) infection with compensated cirrhosis or without cirrhosis who are new to treatment.

The FDA’s approval is supported by an overall 98% cure rate (rates ranged between 92% and 100%) in patients who received the recommended duration of treatment. Patients who achieve a sustained virological response at 12 weeks post-treatment are considered cured. The treatment for genotypes 1 to 6 is approved for use in patients across all stages of chronic kidney disease (CKD) and may be used in up to 95% of HCV patients, depending on stage of liver disease and prior treatment history.

Glecaprevir/pibrentasvir was designed to deliver a cure across all major genotypes and specific treatment challenges, such as patients with severe CKD and genotype 1 patients not cured by an NS5A inhibitor or an NS3/4A protease inhibitor direct-acting antiviral (DAA) treatment, but not both. The medication combines two new DAAs—glecaprevir (100 mg), an NS3/4A protease inhibitor, and pibrentasvir (40 mg), an NS5A inhibitor, dosed once daily as three oral tablets taken with food. The approval is supported by data from nine registrational studies that evaluated more than 2,300 patients of all major HCV genotypes and special populations.

The wholesale acquisition cost (WAC) for eight weeks of Mavyret is $26,400, undercutting competing regimens. The WAC of ledipasvir/sofosbuvir (Harvoni, Gilead Sciences), for example, is $94,500 for 12 weeks or $63,000 for eight weeks. However, the true costs of HCV medications are often dictated by discounts, which may be considerable.

Sources: AbbVie, August 3, 2017; Market watch, August 4, 2017; Red Book, August 28, 2017

Duzallo for Hyperuricemia

The FDA has approved allopurinol/lesinurad (Duzallo, Ironwood Pharmaceuticals) as a once-daily oral treatment for hyperuricemia associated with gout in patients who have not achieved target serum uric acid levels with a medically appropriate daily dose of allopurinol alone. The drug is not recommended for the treatment of asymptomatic hyperuricemia.

The medication combines the standard of care for the treatment of hyperuricemia associated with gout, allopurinol, with the most recently FDA-approved treatment for this condition, lesinurad (Zurampic, Ironwood Pharmaceuticals). The fixed-dose combination provides a dual mechanism of action in one tablet that can address both causes of hyperuricemia— overproduction and underexcretion of serum uric acid. Gout is a highly symptomatic and painful form of inflammatory arthritis caused by hyperuricemia.

The efficacy and safety of lesinurad plus allopurinol were demonstrated in two phase 3 clinical trials. In adults with gout who failed to achieve target serum uric acid levels on allopurinol alone, the lesinurad/allopurinol combination nearly doubled the number of patients who achieved the serum uric acid target of less than 6 mg/dL at month 6, reduced the mean serum uric acid level to less than 6 mg/dL by month 1, and maintained that level through month 12.

The medication has a boxed warning regarding the risk of acute renal failure, which is associated with lesinurad.

Source: Ironwood Pharmaceuticals, August 21, 2017

Gocovri for Parkinson’s Dyskinesia

Extended-release amantadine capsules (Gocovri, Adamas Pharmaceuticals, Inc.) have become the first FDA-approved treatment for dyskinesia in patients with Parkinson’s disease receiving levodopa-based therapy, with or without concomitant dopaminergic medications.

Gocovri is a high-dose 274-mg amantadine (equivalent to 340 mg amantadine hydrochloride [HCl]) taken once daily at bedtime that delivers consistently high levels of amantadine from the morning and throughout the day when dyskinesia occurs based on its unique “chronotherapeutic” profile. It reduces both dyskinesia and off-time in Parkinson’s patients receiving levodopa.

Gocovri’s benefit and safety profile was established in two phase 3 controlled trials in Parkinson’s patients with dyskinesia. In both, patients’ total score on the Unified Dyskinesia Rating Scale was reduced significantly at week 12 compared with placebo: 37% versus 12% in the first study, and 46% versus 16% in the second study. The placebo-adjusted reduction in off-time in both studies was approximately one hour per day.

Amantadine HCl, initially developed as an antiviral medication to treat influenza in the 1960s, has been used previously in combination with levodopa to treat dyskinesias.

Sources: Adamas Pharmaceuticals, Inc., August 24, 2017; National Parkinson Foundation, August 25, 2017

Benznidazole for Chagas Disease

The FDA has granted accelerated approval to benznidazole (Chemo Research, S.L.) for use in children 2 to 12 years of age with Chagas disease. This is the first approved U.S. treatment for Chagas disease (also called American trypanosomiasis), a parasitic infection caused by Trypanosoma cruzi.

The safety and efficacy of benznidazole were established in two placebo-controlled clinical trials in pediatric patients 6 to 12 years of age. The number of children treated with benznidazole who had an antibody test change from positive to negative compared with placebo was approximately 60% versus 14% in the first trial and approximately 55% versus 5% in the second trial.

Source: FDA, August 29, 2017

Kedrab for Rabies Prophylaxis

Rabies immune globulin (human) (Kedrab, Kedrion Biopharma/Kamada Ltd.) has received FDA approval for passive, transient post-exposure prophylaxis of rabies infection when given immediately after contact with a rabid or possibly rabid animal. The product should be administered concurrently with a full course of rabies vaccine.

The efficacy of Kedrab administered concurrently with rabies vaccine was studied in a single-center, randomized, comparator-controlled clinical study. Kamada has been selling the product since 2006 outside of the U.S. under the brand name KamRAB.

Source: Kedrion Biopharma/Kamada Ltd., August 25, 2017

Cyltezo, a Humira Biosimilar

Adalimumab-adbm (Cyltezo, Boehringer Ingelheim) has become the second FDA-approved biosimilar to Humira (AbbVie). Cyltezo, a tumor necrosis factor (TNF) blocker administered by injection from a prefilled syringe, was approved for rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, and plaque psoriasis of varying severity in different populations.

The FDA approval is based on analytical, pharmacological, nonclinical, and clinical development studies demonstrating that Cyltezo is biosimilar to Humira. Cyltezo is not yet commercially available; Boehringer Ingelheim is engaged in patent litigation with AbbVie. Boehringer Ingelheim plans to seek approval for an autoinjector of Cyltezo.

Adalimumab-adbm carries boxed warnings for an increased risk of serious infections, such as tuberculosis; in addition, lymphoma and other malignancies, some fatal, have been reported in children and adolescents treated with TNF blockers.

Another Humira biosimilar, Amgen’s adalimumab-atto (Amjevita) was approved by the FDA in September 2016.

Sources: FDA, August 25, 2017; Boehringer Ingelheim, August 29, 2017

Generic Approval

Isoproterenol Hydrochloride Injection

The FDA has approved the first generic version of isoproterenol hydrochloride injection (Isuprel, Valeant), which helped fuel debate over pharmaceutical costs when Valeant raised the price more than 300% after buying the six-decade-old drug in 2015.

Nexus Pharmaceuticals’ isoproterenol hydrochloride injection, which received expedited FDA review, is available as a single-dose vial containing 0.2 mg/1 mL or 1 mg/5 mL.

The drug is indicated for mild or transient episodes of heart block that do not require electric shock or pacemaker therapy; for serious episodes of heart block and Adams-Stokes attacks (except when caused by ventricular tachycardia or fibrillation); for use in cardiac arrest until electric shock or pacemaker therapy is available; for bronchospasm occurring during anesthesia; and as an adjunct to fluid and electrolyte replacement therapy and the use of other drugs and procedures in the treatment of hypovolemic and septic shock, hypoperfusion states, congestive heart failure, and cardiogenic shock.

Sources: FDA, August 8, 2017; Nexus Pharmaceuticals, August 3, 2017; Fierce-Pharma, August 7, 2017

NEW INDICATIONS

Lynparza for Additional Ovarian Cancer Cases

Olaparib (Lynparza, AstraZeneca/Merck) has received FDA approval for a broader indication in ovarian cancer cases, including a new tablet formulation that will ease women’s pill burden.

Olaparib tablets have been approved as a maintenance treatment for women with recurrent, epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy, regardless of BRCA status. Two of the newly approved tablets can be taken twice daily as opposed to eight capsules twice daily.

The FDA also converted olaparib’s accelerated approval to full approval for use in women with deleterious or suspected deleterious germline BRCA-mutated advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy. Patients for this indication are selected for therapy based on an FDA-approved companion diagnostic.

Two randomized trials supported the new approvals and the conversion of accelerated approval to full approval, which was originally based on a single-arm trial.

Lynparza received FDA accelerated approval in December 2014 as the first poly(ADP-ribose) polymerase inhibitor. Olaparib capsules are not indicated for maintenance therapy. Providers should not substitute olaparib tablets with olaparib capsules on a milligram-to-milligram basis due to differences in the dosing and bioavailability of each formulation.

Source: AstraZeneca, August 17, 2017

Victoza to Reduce CV Risks

Liraglutide (Victoza, Novo Nordisk) has secured FDA approval for a new indication to reduce the risk of major adverse cardiovascular (CV) events—heart attack, stroke, and CV death—in adults with type-2 diabetes and established CV disease.

The FDA’s decision is based on the results of the LEADER trial, which demonstrated that liraglutide significantly reduced the risk of a three-component endpoint consisting of CV death, nonfatal heart attack, or nonfatal stroke by 13% versus placebo (P = 0.01), with an absolute risk reduction (ARR) of 1.9%.

Adults with type-2 diabetes are up to four times more likely to develop CV disease, their leading cause of death. Liraglutide demonstrated a life-saving benefit that included a 22% reduction in CV death and a 15% reduction in all-cause death (ARR, 1.3% and 1.4%, respectively).

Liraglutide is a human glucagon-like peptide-1 analogue that was approved by the FDA in January 2010 as an adjunct to diet and exercise to improve glycemic control in adults with type-2 diabetes.

Source: Novo Nordisk, Inc., August 25, 2017

Faslodex for Breast Cancer Monotherapy

The FDA has approved fulvestrant (Faslodex, AstraZeneca) as monotherapy for expanded use in women with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER−) advanced breast cancer who have gone through menopause and have not received previous endocrine therapy.

The approval is based on data from the phase 3 FALCON trial, which included 462 postmenopausal women with HR+ metastatic or locally advanced breast cancer. The results showed a statistically significant increase in investigator-assessed median progression-free survival, representing a 20% reduction in the risk of disease progression or death determined by RECIST criteria, compared with the aromatase inhibitor anastrozole (Arimidex, AstraZeneca).

Fulvestrant is a hormonal therapy that targets the estrogen receptor (ER), which can influence the growth of HR+ metastatic breast cancer, and helps to slow cancer growth by blocking the ER and targeting it for degradation.

First approved in 2002, fulvestrant has been used as a monotherapy for the treatment of postmenopausal women with HR+ metastatic breast cancer whose cancer has progressed following prior antiestrogen therapy. In 2016, fulvestrant was approved by the FDA in combination with palbociclib (Ibrance, Pfizer) for the treatment of women with HR+, HER2− advanced or metastatic breast cancer whose cancer has progressed after endocrine therapy.

Source: AstraZeneca, August 28, 2017

Actemra for CAR T-Cell–Linked CRS

Tocilizumab intravenous injection (Actemra, Genentech) has received FDA approval for the treatment of chimeric antigen receptor (CAR) T-cell–induced severe or life-threatening cytokine release syndrome (CRS) in patients 2 years of age and older. CRS, which is caused by an overactive immune response, has been identified as a potentially severe and life-threatening side effect of CAR T-cell therapy for certain cancers.

The approval is based on a retrospective analysis of pooled outcomes data from clinical trials of CAR T-cell therapies for blood cancers, which assessed the efficacy of tocilizumab in the treatment of CRS. The study population included 45 pediatric and adult patients treated with tocilizumab, with or without additional high-dose corticosteroids, for severe or life-threatening CRS.

Sixty-nine percent of patients achieved a response, defined as resolution of CRS within 14 days of the first dose of tocilizumab, no more than two doses of tocilizumab needed, and no drugs other than tocilizumab and corticosteroids used for treatment. A second study confirmed resolution of CRS within 14 days using an independent cohort that included 15 patients with CAR T-cell–induced CRS.

Source: Genentech, August 30, 2017

NEW FORMULATIONS

Oral Liquid Spironolactone

Spironolactone oral suspension, 25 mg/5 mL (CaroSpir, CMP Pharma) has become the first FDA-approved oral liquid dosage form of the potassium-sparing diuretic spironolactone.

The new formulation provides a stable, ready-to-use, and consistent liquid treatment option for adults, especially those who have difficulty swallowing or who are unable to swallow tablets. Until now, these patients have been prescribed a pharmacy-compounded liquid form of spironolactone.

Spironolactone oral suspension is indicated for the treatment of New York Heart Association Class III–IV heart failure with reduced ejection fraction to increase survival, manage edema, and reduce the need for hospitalization for heart failure, and is usually administered in conjunction with other therapies. Spironolactone oral suspension is also indicated for use as an add-on therapy for the treatment of hypertension, to lower blood pressure in adults who are not adequately controlled on other agents, and as part of comprehensive cardiovascular risk management. Lastly, it is indicated for the management of edema in adult cirrhotic patients when edema is not responsive to fluid and sodium restriction.

Source: CMP Pharma, August 7, 2017

FDA REVIEW ACTIVITIES

Breakthrough Therapy Status

Imfinzi for Advanced Unresectable NSCLC

AstraZeneca has received a break-through therapy designation for durvalumab (Imfinzi), an anti-programmed death ligand-1 monoclonal antibody being investigated for the treatment of locally advanced unresectable non–small-cell lung cancer (NSCLC).

The breakthrough therapy designation was granted on the basis of interim results from a phase 3, double-blind, placebo-controlled, multicenter trial of durvalumab as sequential treatment in patients with stage III NSCLC who had not progressed following platinum-based chemotherapy concurrent with radiation therapy.

In May 2017, durvalumab received accelerated approval for the treatment of locally advanced or metastatic urothelial carcinoma that has progressed during or following platinum-containing chemotherapy, or within 12 months of receiving platinum-containing chemotherapy before or after surgery.

Phase 3 trials are also under way to test durvalumab as adjuvant therapy for NSCLC, as monotherapy for patients with advanced NSCLC, and in combination with tremelimumab, an anti-CTLA-4 monoclonal antibody.

Source: AstraZeneca, July 31, 2017

Acalabrutinib for Mantle Cell Lymphoma

The FDA has granted breakthrough therapy status to acalabrutinib (Astra-Zeneca/Acerta Pharma) for patients with mantle cell lymphoma (MCL) who have received at least one prior therapy for the disease, which is an aggressive B-cell non-Hodgkin’s lymphoma with poor prognosis. The FDA granted the designation based on clinical data from the acalabrutinib development program, including a phase 2 clinical trial in patients with relapsed or refractory MCL.

Acalabrutinib, a potent, irreversible, highly specific Bruton tyrosine kinase inhibitor, is in development for the treatment of multiple B-cell cancers. More than 25 acalabrutinib clinical trials with more than 2,000 patients are under way or complete. The development program also includes both monotherapy and combination therapy strategies in chronic lymphocytic leukemia, Waldenström macroglobulinemia, follicular lymphoma, diffuse large B-cell lymphoma, multiple myeloma, and solid tumors.

Source: AstraZeneca/Acerta Pharma, August 1, 2017

Mogamulizumab for Mycosis Fungoides and Sézary Syndrome

Kyowa Hakko Kirin Co., Ltd., has received breakthrough therapy status for its investigational product mogamulizumab, which is being developed for the treatment of mycosis fungoides and Sézary syndrome in adults who have received at least one systemic therapy.

Mycosis fungoides and Sézary syndrome are the most common subtypes of cutaneous T-cell lymphoma (CTCL), a rare type of non-Hodgkin’s lymphoma characterized by localization of malignant T lymphocytes to the skin. Depending on the stage, the disease may involve skin, blood, lymph nodes, and viscera. Mogamulizumab is a humanized monoclonal antibody directed against a specific chemokine receptor that is frequently expressed on the leukemic cells of certain hematologic malignancies, including CTCL.

The FDA designation was granted based on data from the MAVORIC study, with 372 patients randomly assigned to receive either mogamulizumab or vorinostat (Zolinza, Merck).

Source: Kyowa Hakko Kirin Co., Ltd., August 25, 2017

Priority Review Designations

Evolocumab for Reducing Risk Of Cardiovascular Events

The FDA has granted priority review for Amgen’s supplemental biologics license application for evolocumab (Repatha), a proprotein convertase subtilisin/kexin type 9 inhibitor. If it is approved, the prescribing information for evolocumab will be updated to include risk reduction of major cardiovascular events. The FDA also accepted a second application seeking to expand the lipid-lowering indication to include additional patient populations.

Evolocumab increases the number of low-density lipoprotein (LDL) receptors available to clear LDL from the blood, thereby lowering LDL cholesterol (LDL-C) levels. The 27,564-patient FOURIER study demonstrated that adding evolocumab to optimized statin therapy resulted in a statistically significant 20% reduction in major adverse cardiovascular events, including time to first heart attack, stroke, or cardiovascular death. The study also found a statistically significant 15% reduction in the risk of hospitalization for unstable angina, coronary revascularization, heart attack, stroke, or cardiovascular death.

The magnitude of risk reduction in both the primary and secondary composite endpoints grew over time, with the robust benefit starting as early as six months and accruing through the median 2.2 years of the study.

No new safety concerns were identified in roughly 60,000 patient-years of follow-up; this included the assessment of patients who achieved very low levels of LDL-C. In particular, there were no notable differences between treatment arms in the overall rate of adverse events, serious adverse events, or adverse events leading to study drug discontinuation.

The FDA has set a Prescription Drug User Fee Act action date of December 2, 2017.

Source: Amgen, July 27, 2017

Injectable Buprenorphine For Opioid Use Disorder

Indivior has been granted a priority review designation for the new drug application (NDA) for RBP-6000, an investigational once-monthly injectable buprenorphine, as part of a complete treatment plan for moderate-to-severe opioid use disorder that includes counseling and psychosocial support.

As a depot injectable formulation, RBP-6000 uses a delivery system (Atrigel) designed to make abuse and diversion difficult. The product is intended to be administered only by health care professionals.

The NDA is based on data from a pivotal phase 3 study assessing the efficacy and safety of RBP-6000. If approved, RBP-6000 would be the first once-monthly injectable buprenorphine treatment for opioid use disorder.

Source: Indivior, July 31, 2017

Tezacaftor/Ivacaftor Combination Treatment for Cystic Fibrosis

The FDA has granted priority review to Vertex Pharmaceuticals’ new drug application for the use of tezacaftor and ivacaftor as a combination treatment in people with cystic fibrosis (CF) who have the F508del mutation. The combination treatment also received a breakthrough therapy designation. The submissions are supported by positive results from two global phase 3 studies.

In CF, a defective or missing cystic fibrosis transmembrane conductance regulator (CFTR) protein (resulting from mutations in the CFTR gene) causes poor flow of sodium and water into and out of the cells in the lungs. This leads to the buildup of abnormally thick, sticky mucus that can cause chronic lung infections and progressive lung damage. The median age of death is in the mid-to-late 20s. In people with the F508del mutation, the CFTR protein is not processed normally within the cell and generally does not reach the cell surface. Tezacaftor is designed to address that processing defect to enable F508del CFTR to reach the cell surface, where ivacaftor can further enhance the protein’s function.

The FDA has set an action date of February 28, 2018.

Source: Vertex, August 24, 2017

Zelboraf for Erdheim-Chester Disease

The FDA has accepted Genentech’s supplemental new drug application (sNDA) for priority review of vemurafenib (Zelboraf) for Erdheim-Chester disease (ECD) with BRAF V600 mutation. ECD is a rare, serious blood disease characterized by the abnormal multiplication of certain white blood cells (histiocytes). Vemurafenib was also granted breakthrough therapy designation for this indication. There are no FDA-approved treatments for ECD.

BRAF is a protein in a cell-signaling pathway that helps control cell growth and survival. Vemurafenib, already indicated for metastatic melanoma, is designed to inhibit some mutated forms of BRAF. It was the first approved product in its class.

The sNDA includes data from the open-label, phase 2 VE-BASKET study. Final results for the 22 patients with ECD showed a best overall response rate of 54.5%. Median duration of response, progression-free survival, and overall survival were not reached at a median follow-up of 26.6 months.

The FDA has set an action date of December 7, 2017.

Source: Genentech, August 7, 2017

Emicizumab for Hemophilia A with Inhibitors

The FDA has granted priority review for emicizumab (Genentech) prophylaxis as a once-weekly subcutaneous treatment for adults, adolescents, and children with hemophilia A with factor VIII inhibitors.

Nearly one in three people with hemophilia A develops inhibitors to standard factor VIII replacement therapies, which limits treatment options and increases the risk of life-threatening bleeds and repeated bleeds that cause long-term damage. Emicizumab is an investigational bispecific monoclonal antibody that brings together factors IXa and X, proteins required to activate the natural coagulation cascade and restore the blood-clotting process.

The biologics license application for emicizumab is based on results from two phase 3 studies (HAVEN 1 and 2). In HAVEN 1, emicizumab prophylaxis produced a clinically meaningful and statistically significant reduction in treated bleeds of 87% compared with on-demand bypassing agents, as well as a statistically significant reduction of 79% in treated bleeds. Interim results from the single-arm HAVEN 2 study were consistent with the positive results from the HAVEN 1 study.

The FDA is expected to make a decision on approval by February 23, 2018.

Source: Genentech, August 24, 2017

Adcetris for Cutaneous T-Cell Lymphoma

The FDA has accepted a supplemental biologics license application for brentuximab vedotin (Adcetris, Seattle Genetics) in patients with cutaneous T-cell lymphoma (CTCL). The agency granted the application priority review.

Results from the phase 3 ALCANZA trial in 128 CTCL patients requiring systemic therapy included highly statistically significant improvement in the rate of objective response lasting at least four months (56.3% compared with 12.5% in the control arm). Key secondary endpoints, including complete response rate, progression-free survival, and reduction in symptoms, were all highly statistically significant in favor of the brentuximab vedotin arm.

Brentuximab vedotin is an antibody–drug conjugate, comprising an anti-CD30 mono clonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE). The antibody–drug conjugate employs a linker system designed to be stable in the bloodstream but to release MMAE upon internalization into CD30-positive tumor cells.

The Prescription Drug User Fee Act target action date is December 16, 2017.

Source: Seattle Genetics, August 16, 2017

Epinephrine Autoinjector for Anaphylaxis in Infants and Children

Kaléo has been granted priority review of its supplemental new drug application (sNDA) for AUVI-Q 0.1 mg, the first known epinephrine autoinjector specifically designed for response to life-threatening allergic reactions in infants and small children.

AUVI-Q 0.1 mg contains a lower dose of epinephrine than the existing auto-injectors (which contain 0.15 mg or 0.3 mg) to avoid giving too much epinephrine. It also has a shorter needle to help reduce the risk of needle striking bone, impacting the delivery of epinephrine.

In anaphylaxis emergencies, individuals without medical training often have to deliver potentially life-saving epinephrine. AUVI-Q is the only compact epinephrine autoinjector with a voice instruction system that helps guide patients and caregivers step by step through the injection process, and a needle that automatically retracts following administration.

If approved, AUVI-Q 0.1 mg is projected to be available for patients in the first half of 2018.

Source: Kaléo, July 27, 2017

Orphan Drug Designations

Odiparcil for Maroteaux-Lamy Syndrome

Inventiva has received an FDA orphan drug designation for odiparcil (formerly IVA336) for the treatment of Maroteaux-Lamy syndrome (MPS VI), a rare pediatric genetic degenerative disease caused by deficiency of the enzyme N-acetyl-galactosamine 4-sulfatase.

Dermatan sulfate and chondroitin sulfate accumulate in the cells, tissues, and organs of MPS VI patients, often causing severe, progressive symptoms that begin early in life. The life expectancy of patients with untreated severe MPS VI is approximately 20 years. There is no cure.

Odiparcil, an orally available therapy, acts on all three alpha, gamma, and delta peroxisome proliferator-activated receptors, which play key roles in controlling the fibrotic process. First patient enrollment in a 26-week phase 2a study is expected by the end of 2017.

Source: Inventiva, August 10, 2017

AMO-02 for Congenital Myotonic Dystrophy

The FDA has awarded AMO Pharma an orphan drug designation for AMO-02, an investigational therapy for the treatment of congenital myotonic dystrophy.

Myotonic dystrophy is the most common form of muscular dystrophy, affecting approximately one in 8,000 people. It is a progressive disease with symptoms that include muscle weakness, intellectual and developmental impairment, and behavioral changes. There are currently no approved therapies for the condition.

A phase 2 clinical trial for AMO-02 has begun in the United Kingdom.

Source: AMO Pharma, July 27, 2017

SENS-401 for Platinum-Induced Ototoxicity

Sensorion has received the FDA’s orphan drug designation for SENS-401 for the prevention of platinum-induced ototoxicity in pediatric patients. As many as 60% of patients develop severe hearing loss due to platinum-based chemo therapies. There is no approved pharmaceutical treatment.

SENS-401 (R-azasetron besylate) is designed to protect and preserve inner ear tissue when lesions may cause progressive hearing impairments. The drug (both oral and injectable) is also in development for the treatment of sudden sensorineural hearing loss. Sensorion expects to initiate a phase 2 clinical trial in this indication in the first half of 2018.

Source: Sensorion, August 22, 2017

SY-1425 for Acute Myeloid Leukemia

The FDA has granted Syros Pharmaceuticals an orphan drug designation for SY-1425, an oral first-in-class selective retinoic acid receptor alpha agonist for the treatment of acute myeloid leukemia (AML).

Syros has identified proprietary biomarkers related to “super-enhancers” that are believed to drive overexpression of the RARA or IRF8 genes in AML and myelodysplastic syndrome (MDS). The overexpression locks cells in an immature, undifferentiated, and proliferative state, leading to disease.

In preclinical studies, SY-1425 promoted differentiation of AML cells with high RARA or IRF8 expression, inhibiting tumor growth and prolonging survival in patient-derived xenograft models of AML with high RARA expression. Syros estimates that about one-third of AML and MDS patients have the RARA biomarker, the IRF8 biomarker, or both. An ongoing phase 2 clinical trial is assessing the safety and efficacy of SY-1425.

Source: Syros Pharmaceuticals, August 21, 2017

H3B-8800 for Leukemia

H3 Biomedicine, Inc., has received an orphan drug designation for H3B-8800 for the treatment of patients with acute myelogenous leukemia (AML) and chronic myelomonocytic leukemia (CMML).

AML and CMML start in the bone marrow and usually move into the blood. H3B-8800 is a potent, selective, and orally bioavailable small-molecule modulator of wild-type and mutant SF3b complexes. In preclinical studies, H3B-8800 showed dose-dependent modulation of canonical and aberrant splicing when dosed orally at tolerated doses. H3 Biomedicine’s lead research and discovery programs in splicing are designed to develop drugs that target the vulnerabilities related to deregulated RNA homeostasis in cancer.

Source: H3 Biomedicine, August 14, 2017

EPX-300 for Dravet Syndrome

Epygenix Therapeutics, Inc., has received an orphan drug designation for EPX-300 for patients with Dravet syndrome, a form of epilepsy. EPX-300 is already FDA approved for major depressive disorder.

Dravet syndrome begins in infancy with frequent or prolonged seizures that cannot be controlled by available medications. In most cases, Dravet syndrome is caused by heterozygous de novo mutations or gene deletions of SCN1A, a gene encoding a brain voltage-gated sodium channel (Nav1.1). In models using zebrafish, EPX-300 suppressed spontaneous convulsive behavior and electrographic seizures.

Source: Epygenix, August 23, 2017

Trans-Resveratrol for Friedreich’s Ataxia

The FDA has granted an orphan drug designation for trans-resveratrol (Jotrol, Jupiter Orphan Therapeutics) to treat Friedreich’s ataxia (FA), a disease of the nervous system. Although rare, FA is the most common form of hereditary ataxia, affecting about one in 50,000 people in the United States.

Jotrol is a patented formulation of trans-resveratrol. Preclinical data indicate that Jotrol delivers the necessary high levels of resveratrol in plasma without generating severe gastrointestinal side effects, which had been a serious drawback to the drug’s use.

Source: Jupiter Orphan Therapeutics, August 22, 2017

Cobitolimod for Pediatric Ulcerative Colitis

The FDA has granted orphan drug status to the drug candidate cobitolimod (InDex Pharmaceuticals) for treatment of ulcerative colitis in pediatric patients.

Cobitolimod, a Toll-like receptor 9 agonist, has an anti-inflammatory effect locally in the large intestine, which may induce mucosal healing and relief of symptoms. Also known as Kappaproct and DIMS0150, cobitolimod has achieved clinical proof-of-concept in moderate-to-severe active ulcerative colitis, with a favorable safety profile. Data from placebo-controlled clinical trials indicate that cobitolimod has statistically significant effects on key clinical symptoms, such as blood in stool, number of stools, and mucosal healing.

Source: InDex Pharmaceuticals, August 9, 2017

Brimonidine Tartrate for Ocular GVHD

Ocugen, Inc., has received the first U.S. orphan drug designation for treating ocular graft versus host disease (oGVHD). About half of patients develop oGVHD as a complication of allergenic hematologic stem cell transplantation or bone marrow transplant. Driven by autoimmune inflammation, oGVHD induces severe ocular surface disease, which over time significantly diminishes quality of life.

OCU300 (brimonidine tartrate) is a repurposed drug being developed through the FDA’s 505(b)(2) pathway for the treatment of oGVHD. According to a post-hoc analysis of OCU300 administered to patients with oGVHD in an exploratory observational study, approximately 90% of patients saw beneficial results without significant adverse effects.

Source: Ocugen, August 9, 2017

PLX-200 for LINCL

The FDA has granted an orphan drug designation for PLX-200 (Polaryx Therapeutics) to treat late infantile neuronal ceroid lipofuscinosis (LINCL), an autosomal recessive neurodegenerative disorder with life expectancy ranging from 6 years to the early teen years. Currently, no patient-friendly treatments are available.

LINCL, which is caused by mutations in the Cln2 gene, leads to the deficiency and/or loss of function of tripeptidyl peptidase 1 (TPP1), which causes auto-fluorescent storage materials to build up in neurons and other cells. Symptoms start with seizures, followed by regression of development, myoclonic ataxia, pyramidal signs, and visual impairment.

PLX-200 is a repurposed drug with a mode of action that includes upregulating the expression of TPP1 mRNA in brain cells and activating production of genes involved in lysosome biogenesis.

Source: Polaryx Therapeutics, August 7, 2017

HBV-Specific Liver Cancer Drugs

The FDA has granted orphan drug designations to Lion TCR for two T-cell therapy product candidates. Both are hepatitis B virus (HBV)-specific therapies to treat hepatocellular carcinoma (HCC).

HCC is the world’s third leading cause of death due to cancer. Globally, 60% of HCC is a result of chronic HBV infection. The general prognosis is poor, with overall survival rates of 3% to 5%.

According to the company, using a proprietary T-cell receptor (TCR) platform, the patient’s T cells are engineered with high-avidity antiviral TCRs, which recognize tumor-specific viral peptides, leading to the release of cytolytic molecules and the lysis of cancer cells.

Source: Lion TCR, August 16, 2017

OMS721 for IgA Nephropathy

The FDA has granted an orphan drug designation for OMS721, a human monoclonal antibody for the treatment of immunoglobulin A (IgA) nephropathy. IgA nephropathy is the most common primary glomerulopathy, and up to 40% of patients develop end-stage renal disease within 20 years of diagnosis.

OMS721 targets MASP-2, a novel pro-inflammatory protein involved in activation of the complement system. Inhibition of MASP-2 does not appear to interfere with the antibody-dependent classical complement activation pathway, a critical component of the acquired immune response to infection.

Phase 2 clinical trial results in IgA nephropathy patients show unprecedented reductions in urine protein levels during and following treatment with OMS721. Based on those data, the FDA also granted OMS721 breakthrough therapy designation for this indication in June. An ongoing phase 2 study is evaluating OMS721 in glomerulonephropathies, and Omeros plans to begin a phase 3 registration trial in IgA nephropathy later this year.

Source: Omeros Corp., August 4, 2017

RA101495 for Paroxysmal Nocturnal Hemoglobinuria

The FDA has granted an orphan drug designation to Ra Pharma for RA101495, a self-administered subcutaneous injection for the treatment of paroxysmal nocturnal hemoglobinuria (PNH). In this chronic, life-threatening blood disorder, red blood cells are attacked and destroyed by the complement system. RA101495 is a synthetic macrocyclic peptide inhibitor of complement component 5. Initial phase 2 data in PNH patients showed nearcomplete inhibition of hemolysis and a favorable safety and tolerability profile.

Source: Ra Pharmaceuticals, July 31, 2017

DRUG SAFETY ISSUES

PharmaTech Products Recalled

The FDA has warned against the use of 22 liquid drug and dietary supplement products made by a Florida company due to potential contamination with Burkholderia cepacia and the risk for severe infection.

The products were made by Pharma-Tech LLC of Davie, Florida, and labeled by Rugby Laboratories, Major Pharmaceuticals, and Leader Brands. The products range from stool softeners to liquid multivitamins marketed for infants and children; they were distributed nation-wide to retailers, health care facilities, and pharmacies and sold online.

The FDA said laboratory testing of PharmaTech’s oral liquid docusate detected a strain of B. cepacia linked to patient infections. In 2016, the FDA advised health care professionals and patients not to use liquid docusate drug products manufactured at PharmaTech’s Davie facility after it was implicated in a public health investigation of a B. cepacia outbreak.

Sources: FDA, August 8 and August 11, 2017

DEVICE APPROVALS

StimQ Peripheral Nerve Stimulator

The StimQ peripheral nerve stimulator (Stimwave LLC) has received 510(k) clearance as the first wireless microtechnology neuromodulation device that can remain in patients’ bodies as they undergo full-body MRI scans under certain conditions.

The StimQ peripheral nerve stimulator system can be placed in a minimally invasive outpatient procedure for the treatment of various pain syndromes, such as shoulder pain, upper extremity neuropathy, mid and lower back pain, and lower extremity neuropathy.

While studies have shown peripheral nerve stimulation to be effective, device placement has been difficult due to the bulk and length of cables, connectors, and pulse generators needed to stimulate a small nerve target. Stimwave says its new device is less than 5% of the size of other standard implanted options.

The multielectrode programmable device delivers small pulses of energy in a fully selectable manner to electrodes placed at a peripheral nerve, enabling the brain to remap specific pain signals. The implant is powered by a small, flexible, wearable external unit. The company previously received FDA clearance for the Freedom-8A/4A spinal cord stimulation system, which is also cleared for full-body MRI scans and utilizes the same technology specifically for back and leg pain based on placements in the spinal column region.

Source: Stimwave, August 9, 2017

Abbott MagLev LVAD

The FDA has approved Abbott’s Full MagLev HeartMate 3 left ventricular assist device (LVAD) for advanced heart failure patients who need short-term hemodynamic support (bridge to transplant or bridge to myocardial recovery). The system’s pump uses magnetic levitation to reduce trauma to the blood passing through it.

For advanced heart failure patients who can no longer rely on earlier-stage treatment options, an LVAD can help the weakened heart pump blood through the body as patients await further treatment.

In the MOMENTUM 3 clinical study, patients who received the HeartMate 3 had a significant improvement in their heart failure status, an 83% increase in their walk distance, and a 68% improvement in quality of life at six months. No suspected or established blood clotting within the pump was reported at six months. The study includes more than 1,000 patients with New York Heart Association class IIIB or IV heart failure who were followed for a short-term endpoint of six months and continue to be followed for a long-term endpoint of two years.

In traditional LVADs, bearings can damage blood passing through a mechanical pump. The HeartMate 3’s fully magnetically levitated flow technology allows the device rotor to be “suspended” by magnetic forces rather than bearings to more gently pass blood through the pump. The magnets keep the rotor in place by calibrating tens of thousands of times per second to ensure it stays suspended and centered in the pump.

The system has the industry’s widest pump pathway so blood cells are not damaged, Abbott says. A built-in “pulse” helps ensure the blood continues to move without becoming static, reducing the risk of blood clot formation. Abbott also reduced the size of the system, which includes the LVAD pump as well as an external, wearable controller, driveline, and battery system that powers the pump.

Source: Abbott, August 28, 2017

t:slim X2 Insulin Pump

The FDA has approved the t:slim X2 insulin pump with Dexcom G5 Mobile continuous glucose monitoring (CGM) integration (Tandem Diabetes Care, Inc.) for patients 6 years of age and older. It is the first sensor-augmented insulin pump approved to let users make treatment decisions without pricking their finger.

Software on this pump will also be available to current t:slim X2 pump users at no cost via remote software update, allowing them to add CGM integration to their existing pumps.

The pump displays a user’s insulin delivery activity and Dexcom G5 Mobile CGM data together on a single device. It is up to 38% smaller than other pumps, but includes a large color touchscreen, Bluetooth radio, rechargeable battery, USB connectivity, 300-unit insulin capacity, and watertight construction.

The t:slim X2 pump can operate as a standalone insulin pump without CGM or be paired with Dexcom G5 Mobile CGM to track glucose continuously and display that information directly on the pump’s home screen.

Source: Tandem Diabetes Care, August 28, 2017

Lutonix Balloon Catheter for ESRD

The Lutonix 035 drug-coated balloon PTA catheter (C.R. Bard, Inc.) has received FDA pre-market approval for a new indication: use in patients with endstage renal disease (ESRD) with stenotic lesions in dialysis arteriovenous (AV) fistulae. This latest approval adds to its prior FDA indication for the treatment of superficial femoral artery and popliteal artery disease.

The FDA approval was based on results of the Lutonix AV clinical trial in patients with stenotic lesions in AV fistulae. Follow-up results demonstrated safety with the Lutonix 035 DCB catheter comparable to uncoated balloons. The Lutonix 035 DCB catheter also demonstrated a sustained clinical benefit compared to conventional angioplasty through 12 months.

Source: C.R. Bard, Inc., August 28, 2017